Aryl and heteroaryl ethers as agents for the treatment of hypersensitive ailments

ABSTRACT

The present invention is concerned with the therapeutic composition comprising as an active ingredient a compound of the formula: 
     
         (R.sub.1)(R.sub.2) Ar--Z--M--Ar.sub.1 (R.sub.3)(R.sub.4)   I 
    
     and salts thereof; wherein 
     Ar and Ar 1  are independently phenyl, naphthyl or a nitrogen, oxygen, or sulfur heterocyclic ring; 
     Z is an alkylene chain containing from 1 to 5 carbon atoms in the principal chain and up to a total of 10 carbon atoms; 
     M is oxygen, sulfur, or NR 5  ; 
     R 1 , R 2 , R 3  and R 4  are each independently H, lower alkyl, lower alkoxy, hydroxy, halo, trihalomethyl, hydroxy lower alkyl, carboxy, formyl, aryl, aryloxy, benzyloxy, lower alkanoyl, carboxy lower alkoxy, nitro, amino, lower alkylamino, dilower alkylamino, cyano, lower alkanoyloxy, carbamoyl, lower alkoxy-alkoxy, carbo-lower-alkoxy-alkoxy, or tetrahydropyranylmethyl; and 
     R 5  is hydrogen or lower alkyl.

This application is a division of copending application Ser. No. 723,781filed Apr. 16, 1985, U.S. Pat. No. 4,631,287.

This invention relates to the use of certain chemical compoundspossessing valuable pharmaceutical activity, particularly aslipoxygenase inhibitors possessing anti-inflammatory and anti-allergicproperties

U.S. Pat. Nos. 4,327,102 and 4,394,509 and U.K. Patent Application Ser.No. 2,069,492 describe sulfoxides of the formula: ##STR1## in which R ishydrogen or a hydrocarbon radical, R¹ is H or F, R² is H, F, Cl or CF₃,and n is 1 or 2, as anti-ulcer and/or anti-secretory compounds, as wellas the corresponding thioether compounds which are prepared by oxidationof the thioether sulfur to the sulfone. The thioethers of the saidstructure are also described in U.S. Pat. Nos. 4,415,579, 4,394,509 and4,337,259 as anti-ulcer compounds.

I. Eur. J. Med. Chem.--Chem. Ther- 1983-18 (pp. 277-285), describedcompounds of the following structures as anti-secretory agents: ##STR2##R=various heterocyclics, cyclohexyl, various substituted phenyls; Y=CH₂,S, (CH₂)₂, (CH₂)₃, CHMe, C═O, C═C;

R₂ =H, CHO, CH(OEt)₂ ##STR3## R₁ is benzyloxypyridyl quanternary salts,phenylthiomethyl, benzylsulfoxy, benzylthio, etc. ##STR4## A=alkylene upto C₅, and ##STR5## R₁ and R₂ =various heterocycles, phenyl, substitutedphenyl;

X=--, O, O₂ ##STR6## X=-- or O; R_(n) =H, halogen, or methoxy.

The Journal of the Pharmaceutical Society of Japan, 71, 1275-1277 (1951)describes the synthesis of 2-phenoxymethylquinoline,2-phenoxymethylquinoline-4-carboxylic acid and 3-phenoxy-4-quinolinecarboxylic acid from the condensation of isatin and phenoxyacetone underPfitzinger reaction conditions. No therapeutic properties of thesecompounds were suggested or disclosed by this article.

Fischer, et al. measure the dissociation constant of variousα-substituted -2-picolinium ions and α-substituted-3-picolinium ions inwater in the Canadian Journal of Chemistry, 56, 3059-3067 and 3068-3071(1978), respectively. The phenyl substituted 2- and 3-picolinium ionswere included in their study. Again, there was no suggestion or teachingregarding the therapeutic efficacy of these compounds.

The Journal of Medicinal Chemistry, 26, 218-222, (1983)described2-[(phenylthio)methyl]pyridines and oxides thereof of the followingstructures as potential antiarthritic agents: ##STR7## wherein X ishydrogen, bromo, chloro, fluoro, nitro, t-butyl, methyl, methoxy, amino,acetoamido, hydroxy, trifluoromethyl;

Y is hydrogen, chloro, and t-butyl;

X' is phenyl, chloro, methyl, methoxy, hydroxy, and methylthiophenyl.##STR8## wherein ##STR9##

Roreniki, Chem., 31, 543-51 (1957), teaches the preparation of 2--C₆ H₄NCH₂ SPh. No therapeutic properties of the compounds were disclosed.

Diaryl ethers are also known in the prior art.

Boyer and Wolford in J.A.C.S., 80, 2741-2743 (1958), describe thesynthesis of 2-pyridylmethyl ethers from the reaction of pyridothiazoleand phenol. Pharm. Bull, 4, 211-216 (1956) decribes the synthesis ofpicolyl ethers of the formula 4--PyCH₂ OR, wherein R is lower alkyl,phenyl or benzyl. Neither reference discloses any therapeutic use forthese compounds.

The Journal of Chemical Society, Perkin, I, 418-425 (1979) describes thesynthesis of the compounds possessing the following formula:

    Ar--CH.sub.2 --X--Ar.sub.1

wherein

Ar=Ph, p--MeC₆ H₄, p--ClC₆ H₄, pyridine or napthalene,

X=O, CH₂, S, or SO₂

Ar₁ =pyridine, 4-phenylpyridine, or phenyl.

No physiological application or therapeutic use was disclosed orsuggested by this reference.

Thus, the therapeutic activity of these compounds as ananti-inflammatory or as an anti-allergic agent was not recognized orsuggested by any of these references mentioned hereinabove.

SUMMARY OF THE INVENTION

The present invention is concerned with the therapeutic compositioncomprising as an active ingredient a compound of the formula:

    (R.sub.1)(R.sub.2) Ar--Z--M--Ar.sub.1 (R.sub.3)(R.sub.4)   I

and salts thereof; wherein

Ar and Ar₁ are independently phenyl, naphthyl or a nitrogen, oxygen, orsulfur heterocyclic ring;

Z is an alkylene chain containing from 1 to 5 carbon atoms in theprincipal chain and up to a total of 10 carbon atoms;

M is oxygen, sulfur, or NR₅ ;

R₁, R₂, R₃ and R₄ are each independently H, lower alkyl, lower alkoxy,hydroxy, halo, trihalomethyl, hydroxy lower alkyl, carboxy, formyl,aryl, aryloxy, benxzyloxy, lower alkanoyl, carboxy lower alkoxy; nitro,amino, lower alkylamino, dilower alkylamino, cyano, lower alkanoyloxy,carbamoyl, lower alkoxy-alkoxy, crabo-lower-alkoxy-lower-alkoxy ortetrahydropyranylmethyl; and

R₅ is hydrogen or lower alkyl.

In addition, the present invention relates to the method of using thesecompounds a lipoxygenase inhibitors possessing anti-inflammmatory andanti-allergic responses.

The heterocyclic rings exemplary of Ar and Ar₁ contain at least oneoxygen, sulfur or nitrogen and include the so-called benzoheterocyclicrings. Exemplary heterocyclics include furan, thiophene, pyrrole,pyridine, thiazole, piperazine, oxazole, benzofuran, quinoline,isoquinoline, indole, benzothiophene, benzoxazole, and similarheterocyclic rings as well as the N-oxides of thenitrogen-heterocyclics. The preferred heterocyclic is quinoline.

The alkyl groups, either alone or within the various substituents,defined hereinbefore, are preferably lower alkyl, which may be straightor branched chain and include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, amyl, hexyl and the like.

The halo atoms in halo and trihalomethyl are Cl, Br, I and preferably F.The aryl groups are preferably phenyl.

The preferred compounds are those in which the alkylene chainrepresented by Z contains from 1-3 carbon atoms and is a normal alkylenechain, most preferably, unsubstituted, Ar is quinoline, Ar₁ is phenyland M is O. Of the substituents on Z, the preferred are lower alkyl,e.g., methyl, ethyl and isopropyl.

Further preference exists for compounds in which Z is methylene and R₁,R₂ and R₃ are H, methoxy, or carboxyisopropoxy or lower alkyl estersthereof and R₄ is H, nitro or OCH₃.

The present compounds can be prepared by art-recognized procedures fromknown compounds or readily preparable intermediates. An exemplarygeneral procedure is as follows: ##STR10## wherein R₁, R₂, Ar, Z, M,Ar₁, R₃ and R₄ are as defined above, and L is a leaving group, such ashalo, tosylate, or mesylate. If M is O or S, any base normally employedto deprotonate an alcohol or thiol may be used, such as sodium hydride,sodium hydroxide, triethyl amine, sodium bicarbonate ordiisopropyl/ethylamine.

The above bases may also be used when M is an amine. Reactiontemperature are in the range of room temperature to reflux and reactiontimes vary from 2 to 48 hours. The reaction is carried out in a solventthat will dissolve both reactants and is inert to both as well. Solventsinclude, but are not limited to, diethyl ether, tetrahydrofuran, N,N-dimethyl formamide, dimethyl sulfoxide, dioxane and the like.

As a further variation, the amino derivatives can be prepared bycondensation of an aldehyde ##STR11## (IV) with a primary amine (V) toform the corresponding imine and the imine is reduced to give a compoundof Formula I wherein M is nitrogen and R₅ is hydrogen. This product canbe alkylated with alkylating agents known in the art, such as alkyliodides, to form compounds of Formula I wherein M is nitrogen and R₅ islower alkyl. In this process, R₁, R₂, R₃, R₄, R₅, Ar and Ar₁ are asdefined hereinabove and Z₂ is an alkylene chain containing 0 to 4 carbonatoms.

The aforementioned condensation reaction to form imines with subsequenthydrogenation can be conveniently carried out in a single reaction zoneby the expendiency of mixing the aldehyde (IV) with the amine (V) underhydrogenation conditions. For practical purposes, the aforesaidreactants can be hydrogenated over noble metal catalysts such aspalladium over platinum, rhodium, ruthenium, and the like, and the twostages occur under such conditions to produce the desired end products.Alternatively, the imine can be reduced with Lewis acids, such as NaBH₃CN, sodium borohydride and the like under the above conditions.

As in any organic reaction, solvents can be employed, such as methanol,methylene chloride, chloroform, tetrahydrofuran, dioxane, diethyl ether,ethanol and the like. The reaction is normally effected at or near roomtemperature, although temperatures from 0° C. up to the refluxtemperature of the rection mixture can be employed.

The present compounds form salts with acids when a basic amino functionis present and salts with bases when an acid function, i.e., carboxyl,is present. All such salts are useful in the isolation and/orpurification of the new products. Of particular value are thepharmaceutically acceptable salts with both acids and bases. Suitableacids include, for example, hydrochloric, sulfuric, nitric,benzenesulfonic, toluenesulfonic, acetic, malic, tartaric and the likewhich are pharmaceutically acceptable. Basic salts for pharmaceuticaluse are the Na, K, Ca, and Mg salts.

Various substituents on the present new compounds, e.g., as defined inR, R₁, R₂, and R₃ can be present in the starting compounds, added to anyone of the intermediates or added after formation of the final productsby the known methods of substitution or conversion reactions. If thesubstituents themselves are reactive, then the substituents canthemselves be protected according to the techniques known in the art. Avariety of protecting groups known in the art may be employed. Examplesof many of these possible groups may be found in "Protective Groups inOrganic Synthesis" by T. W. Green, John Wiley and Sons, 1981. Forexample, the nitro groups can be added to the aromatic ring by nitrationand the nitro group converted to other groups, such as amino byreduction, and halo by diazotization of the amino group and replacementof the diazo group. Alkanoyl groups can be substituted onto the arylgroups by Friedel-Crafts acylation. The acyl groups can then betransformed to the corresponding alkyl groups by various methods,including the Wolff-Kishner reduction and Clemmenson reduction. Aminogroups can be alkylated to form mono and dialkylamino groups; andmercapto and hydroxy groups can be alkylated to form correspondingethers. Primary alcohols can be oxidized by oxidizing agents known inthe art to form carboxylic acids or aldehydes, and secondary alcoholscan be oxidized to form ketones. Thus, substitution or alterationreactions can be employed to provide a variety of substituentsthroughout the molecule of the starting material, intermediates, or thefinal product.

The compounds of the present invention can be administered to the hostin a variety of forms adapted to the chosen route of administration,i.e., orally, intravenously, intramuscularly or subcutaneous, topicallyor inhalation routes.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsule, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet For oral therapeutic administration, the active compound may beincorporated with excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, e1ixirs, suspensions, syrups, wafers,and the like Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweehabout 2 to about 60% of the weight of the unit. The amount of activecompound in such therapeutically useful compositions is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 50 and 300 mg of active compound

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compound may be incorporated intosustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperitoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersions canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The following examples further illustrate the invention.

EXAMPLE 1 2-Phenoxymethyl quinoline

A mixture of 2-chloromethyl quinoline (0.05 mol), phenol (0.055 mol),finely powdered potassium carbonate (0.055 mol), cesium carbonate (0.005mol) and sodium iodide (0.0025 mol) in acetone was refluxed for about 4hours. The reaction mixture was cooled to room temperature and filteredand the filtrate was concentrated and dissolved in ether. The ethersolution was washed thoroughly with lN NaOH solution, water and brine.After drying the ether solution over anhydrous magnesium sulfate, andfiltering off the drying agent, the solvent was evaporated off to leavethe crude product which was crystallized from hexane and ether to yieldthe desired compound as a light yellow solid, m.p. 79.5°-80.5° C.

EXAMPLE 2 2-(p-Nitrophenoxymethyl) quinoline

This compound was prepared in an identical manner as described inExample 1, except p-nitrophenol was substituted for phenol, m.p.142°-143° C.

EXAMPLE 3 2-(p-Methoxyphenoxymethyl) quinoline

This compound was prepared in an identical manner as described inExample 1, except p-methoxyphenol was substituted for phenol, m.p.79°-80° C.

In a similar fashion according to the procedures of the precedingexamples, the following compounds can be prepared from approproatestarting materials:

2-phenoxymethyl pyridine;

2-phenoxymethyl furan;

2-phenoxymethyl oxazole;

1-phenoxymethyl isoquinoline;

2-phenoxymethyl indole;

2-phenoxymethyl benzoxazole;

2-phenoxymethyl thiophene;

2-phenylthiomethyl quinoline;

1-phenylthiomethyl isoquinoline;

2-phenylthiomethyl furan;

2-phenylthiomethyl indole;

2-phenylthiomethyl thiophene;

2-phenylaminomethyl pyridine;

2-phenylaminomethyl quinoline;

1-phenylaminomethyl isoquiholine;

2-phenylaminomethyl indole;

2-phenylaminomethyl thiophene;

3-phenoxymethyl quinoline;

3-phenoxyethyl quinoline;

3-phenoxymethyl isoquinoline;

2-(2-pyridyloxymethyl)quinoline;

1-(2-imidazolyloxyethyl)isoquinoline;

2-(3-pyrrolyloxymethyl)quinoline;

2-(2-indoloxymethyl)quinoline;

2-(2-naphthyloxymethyl)quinoline;

2-(2-naphthyloxymethyl)quinoline;

2-(2-thienyloxymethyl)quinoline;

2-(2-furyloxymethylmethyl)quinoline;

2-(2-(benzyloxyphenyl)quinoline;

α-phenoxymethylnaphthalene;

p-phenylthiomethyltoluene;

α-phenylthioethylnaphthalene;

p-phenylaminomethylphenol;

β-phenylaminopropylnaphthalene)

p-(2-pyridyloxymethyl)anisole;

β-(2-imidazolyloxymethylnapthalene)

2-phenylpropyloxythiophene;

2-benzyloxyfuran;

2-benzyloxypyridine.

4-phenoxymethylquinoline

4-phenoxymethylisoquinoline

8-phenoxyquinoline

8-benzyloxyquinoline

2-(2-quinolylmethoxymethyl)quinoline

2-(2-pyridylmethoxymethyl)quinoline

1-(2-quinolylmethoxymethyl)isoquinoline

2-(3-carboxyphenoxymethyl)quinoline

2-(3-cyanophenoxymethyl)quinoline

2-(4-fluorophenoxymethyl)quinoline

2-(3-trifluoromethylphenoxymethyl)quinoline

2-(4-butoxyphenoxymethyl)quinoline

6-methoxy-2-(4-fluorophenoxymethyl)quinoline

8-methoxy-2-(3-trifluoromethylphenoxymethyl)quinoline

1-(3-butoxyphenoxymethyl)isoquinoline

1-(3-butylphenoxymethyl)isoquinoline

6-propionyloxy-2-(3-carboxyphenoxymethyl)quinoline

8-propionyloxy-2-(3-butoxyphenoxymethyl)quinoline

6-carbethoxyisopropoxy-2-(3-carboxyphenoxymethyl)quinoline

8-carbethoxyisopropoxy-2-(3-carboxyphenoxymethyl)quinoline

2-(3-(carbethoxyphenoxy)methyl)quinoline

2-(3-(carboxyphenoxy)methyl)quinoline

2-(3-(cyanophenoxy)methyl)quinoline

1-(3-(trifluoromethylphenoxy)methyl)isoquinoline

1-(3-(fluorophenoxy)methyl)isoquinoline

1-(3-(chlorophenoxy)methyl)quinoline

2-(3-(butoxyphenoxy)methyl)quinoline

2-(m-tolyloxymethyl)quinoline

2-(3-(benzyloxy)methyl)quinoline

2-(4-(phenoxyphenoxy)methyl)quinoline

2-(3,5-dichlorophenoxymethyl)quinoline

2-(3,4-dimethoxyphenoxymethyl)quinoline

2-(4-fluorophenoxymethyl)-6-methoxyquinoline

2-(3-butoxyphenoxymethyl)-6-methoxyquinoline

2-(4-fluorophenoxymethyl)-8-methoxyquinoline

2-(3-carboxyphenoxymethyl)-8-methoxyquinoline

2-(3-carboxyphenoxymethyl)-6-methoxyquinoline

2-(3-trifluoromethylphenoxymethyl)-7-methoxyquinoline

2-(3-chlorophenoxymethyl)-6-methoxyquinoline

8-(3-n-butoxy)benzyloxyquinoline

1-(3-n-butoxyphenoxymethyl)isoquinoline

2-(3-trifluorophenoxy)-6-methoxyquinoline

2-(3-carboxyphenoxy)-7-methoxyquinoline

8-(3-n-butylbenzyloxy)quinoline

1-(3-carboxyphenoxymethyl)isoquinoline

2-(4-(4-tetrahydropyranylmethyl)phenoxymethyl) quinoline

The compounds of the present invention have potent activity inregulating lipoxygenase and as such possess therapeutic value in thetreatment of inflammatory conditions and allergic responses such asanaphlaxis and asthma.

Lipoxygenases in mammals have been found in the lung, platelets, andwhite cells. They are enzymes capable of oxidizing arachidonic acid intohydroperoxyeicosatetraenoic acids (HPETEs) and their stable productshydroxyeicosatetraenoic acids (HETEs). Lipoxygenases are classifiedaccording to the position in the arachidonic acid which is oxygenated.Platelets metabolize arachidonic acid to 12-HETE, whilepolymorphonuclear leukocytes contain 5 and 15 lipoxygenases. It is knownthat 12-HETE and 5, 12-diHETE are chemotactic for human neutrophils andeosinophils, and may augment the inflammation process. 5-HPETE is knownto be a precursor of slow-reacting substance of anaphylaxis (SRS-A). TheSRS family of molecules, such as leukotrienes C, D, and E have beenshown to be potent bronchoconstrictors (see, NATURE 288, 484-486(1980)).

The following protocol describes an assay to detect inhibitors of thelipoxygenase pathway. Such inhibitors are believed to be capable ofmodulating the biosynthesis of the leukotrienes, a property believed tobe useful in treating asthma and inflammatory disease states.

Protocol for Detecting Inhibitors of the Lipoxygenase Pathway

A suspension of rat neutrophils in buffer is incubated for 3 minutes at30° C. with (¹⁴ C)-arachidonic acid (AA) and Calcium Ionophore A23187.Citric acid (2M) is used to quench the reaction. Following the additionof a trace amount of (³ H)-5-HETE together with an excess of unlabeled5-HETE to each tube, the mixture is extracted with chloroform/methanol.The organic layer is washed with dilute acid and an aliquot istransferred to glass tubes and dried. The residue is dissolved in asmall volume of chloroform and an aliquot is spotted on silica gel TLCsheets, which are developed with an ethyl acetate/isooctane/water/aceticacid solvent system. The 5-HETE spots are visualized with iodine, cutout and placed in scintillation vials for counting. After adjusting forthe extraction efficiency, the amount (pmole) of (¹⁴ C)-5-HETE in eachof the tubes is quantitated by substracting the net pmoles of 5-HETE inthe tubes containing buffer along (blank) from the pmoles of 5HETE inthe tubes containing buffer and cells (control). The ability of the testcompounds to modulate the activity of this enzyme is determined by adecrease or increase in the net amount of

-5-HETE produced.

2-Phenoxymethyl quinoline and 2-(p-methoxyphenoxymethyl) quinoline onsuch testing indicated a value of I₅₀ =0.5 μM and 0.7 μM, respectively,illustrating potent inhibiting activity of the present compounds.

Leukotrienes, the products of the 5-lipoxygenase pathway of arachidonicacid metabolism, are potent contractile agents with a variety of smoothmuscle preparations. Thus, it has been hypothesized that theleukotrienes contribute significantly to the pathophysiology of asthma.The following protocol describes an in vitro assay used to testcompounds which specifically antagonize the actions of leukotrienes.

Protocol for SRS-A (slow reacting substance of anaphylaxis) Antagonists

Peripheral strips of guinea pig lungs are prepared and hung in tissuebaths (Metro #ME-5505, 10 ml) according to the publishedprocedure--(Proc. Nat'l Acad. Sci., U.S.A. Volume 77, pp. 4354 - 4358,1980). The strips are thoroughly rinsed in Assay Buffer and thenconnected with surgical silk thread to support rods from the tissuebaths. The rods are adjusted in the baths and the strips connected tothe pressure transducers (Grass FT 103 or Gould UC-3). The tissue bathsare aerated with 95% oxygen - 5% carbon dioxide and maintained at 37° C.The assay buffer has been made as follows: for each liter of buffer thefollowing are added to approximately 800 ml of water distilled inglass-6.87 g NaCl, 0.4 g KCl, 2.1 g NaHCO₃, 0.14 g NaH₂ PO₄.H₂ O, 0.21 gMgSO₄. 7H₂ O, and 2.0 g D-glucose. Then a solution of 0.368 g CaCl₂.2H₂O in 100 ml glass-distilled water is slowly added to the buffer.Sufficient water is added to adjust the volume to one liter, and thesolution is aerated with 95% oxygen-5% carbon dioxide. Usually 10 litersof buffer are used for an experiment with 4 tissues.

After the tissues have been repeatedly washed and allowed to equilibratein the tissue bath, they are challenged with 1 μM histamine. Aftermaximum contractions habe been obtained, the tissues are washed, andallowed to relax back to baseline tension. This histamine challengeprocedure is repeated at least 1 to 2 more times to obtain a repeatablecontrol response. The average response to 1 μM histamine for each tissueis used to normalize all other challenges.

Responses of each tissue to a pre-determined concentration ofleukotriene are then obtained. Usually test compounds are examinedinitially at 30 μM on resting tension of the tissues without any addedagonist or antagonist to determine if the compound has any possibleintrinsic activity. The tissues are washed and the test compound isadded again. Leukotriene is added after the desired pre-incubation time.The intrinsic activity of the compounds, and their effect onleukotriene-induced contractions are then recorded.

The concentration required for 50% inhibition of 0.2 nM leukotriene C₄-induced contraction of guinea pig peripheral strips for 2-phenoxymethylquinoline and 2-(p-methoxyphenoxymethyl)quinoline were 0.9 μM and 0.3 μ,respectively.

Representative compounds of the present invention were also tested inthe following in vivo model. Protocol for in vivo Testing of Modulatorsof SRS-A (slow reacting substances of anaphylaxis).

This test, known as the Bronchial Anaphylaxis in Guinea Pigs withEnhanced Leukotrienes (BAGEL), is based on the procedure published inAgents and Actions, Vol. II, pp. 396-401, 1981, and is performed withguinea pigs actively immunized (14 days) with ovalbumin (2.7 mg/kg,i.p.) and B. pertussis (5×10⁹ organisms) as an adjuvant. Prior tochallenge with antigen (ovalbumin), the animals are anesthetized andprepared for monitoring pulmonary dynamics by whole bodyplethysmography. They are treated with an H¹ antihistamine(methapyrilene, 2mg/kg, i.v.) and cyclooxygenase inhibitor(indomethacin; 20 mg/kg, i.p.) in order to enhance the SRS-A componentof anaphylactic bronchoconstriction. Bronchoconstriction is quantifiedas the maximum increase in airway resistance following antigenchallenge. The drug is administered either i.p. 10 minutes beforechallenge, or i.d. 15 minutes before challenge.

2-Phenoxymethyl quinoline was highly active at 100 mg/kg, i.d.

What is claimed is:
 1. A method for the treatment of hypersensitive,inflammatory or allergic conditions in a mammal, comprising theadministration to said animal of a therapeutically effective amount of acompound having the following formula:

    (R.sub.1)(R.sub.2)Ar--Z--M--Ar.sub.1 (R.sub.3)(R.sub.4)

and salts thereof; wherein Ar and Ar₁ are independently an unsaturatedsulfur heterocyclic ring; Z is an alkylene chain containing from 1 to 5carbon atoms in the principal chain and up to a total of 10 carbonatoms; M is oxygen, sulfur or NR₅ ; R₁, R₂, R₃ and R₄ are eachindependently H, lower alkyl, lower alkoxy, hydroxy, halo,trihalomethyl, hydroxy lower alkyl, carboxy, formyl, aryl, aryloxy,benzxyloxy, carboxy lower alkoxy, nitro,amino, lower alkylamino, diloweralkylamino, cyano, lower alkanoyloxy, carbamoyl, or lower-alkoxy-alkoxy;and R₅ is hydrogen or lower alkylin a pharmaceutically acceptablecarrier.
 2. The method according to claim 1 wherein M is oxygen.
 3. Themethod according to claim 1 wherein Z contains 1 to 2 carbon atoms inthe principal chain, R₁, R₂ and R₃ are H, methoxy, or carboxyisopropoxyor lower alkyl esters thereof and R₄ is H, nitro or methoxy.
 4. Atherapeutic composition for the treatment of hypersensitive,inflammatory or allergic conditions comprising as an active ingredientan effective amount of a compound of a formula

    (R.sub.1)(R.sub.2)Ar----M--Ar.sub.1 (R.sub.3)(R.sub.4)

and salts thereof; wherein Ar and Arl are independently an unsaturatedsulfur heterocyclic ring; Z is an alkylene chain containing from 1 to 5carbon atoms in the principal chain and up to a total of 10 carbonatoms; M is oxygen, sulfur, or NR₅ ; R₁, R₂, R₃ and R₄ are independentlyH, lower alkyl, lower alkoxy, hydroxy, halo, trihalomethyl,hydroxy-lower alkyl, carboxy, formyl, aryl, aryloxy, benzxyloxy, carboxylower alkoxy, nitro, amino, lower alkylamino, dilower alkylamino, cyano,lower alkanoyloxy, carbamoyl, or lower alkoxy-alkoxy, and R₅ is hydrogenor lower alkyl in a pharmaceutically acceptable carrier.
 5. Thetherapeutic composition according to claim 1 wherein M is oxygen.
 6. Thetherapeutic composition according to claim 4 wherein Z contains one totwo carbon atoms in the principal chain, R₁, R₂, R₃ are each H, methoxyor carboxy isopropoxy or lower alkyl esters thereof and R4 is H, nitroor methoxy.